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An Ultrasound-Activated Nanoparticle Vehicle for Selective Imaging and Drug Delivery

This project will develop a dual imaging and drug delivery system. Our technology involves a nanoparticle in which a small molecule MRI contrast agent is anchored in the core and the periphery is coated with a selectively removable shell that masks the particle’s MRI contrast properties until it is removed. Additionally, our particle can encapsulate a small molecule drug and limit its ability to escape from its carrier until the desired time and place. The particle’s shell is designed to be removed by clinical ultrasound, which is applied externally. Thus, we are inventing a combined imaging and therapy system that is activated on command deep within the tissue, which will allow simultaneous activation of imaging contrast and delivery of a therapeutic agent.

We will construct phosphate-covered nanoparticles of variable size that contain an MRI contrast agent, load them (non-covalently) with lipophilic drugs, then apply a shell that will simultaneously keep the drug in and hold water out, so that the MRI contrast agent is masked. In principle, once IV injected into patients, this construct should aggregate in tumors because of size-exclusion effects of Enhanced Permeability and Retention (EPR). The particles can then be activated by ultrasound with simultaneous drug release and MRI contrast enhancement.

Innovation and Significance
This project will develop a “smart theragnostic” system that is simultaneously an externally activated imaging agent and an externally activated drug delivery system. As regards the former, several “smart” MRI contrast agents have been reported; these are agents that are responsive to their environment. Our strategy is fundamentally different because it is activated by external ultrasound, rather than environment. This has huge value because ultrasound is a rare form of radiation that can penetrate deep within tissue while causing minimal tissue damage.

Development of dual imaging and therapeutic systems is an emerging topic in medicine; “A main challenge in nanobiomedicine is the design of monodisperse and uniform nanomaterials with a size less than 100 nm that can efficiently encapsulate anti-cancer drugs at a high load and sustain-release their cargo at target sites.” Moreover, “Nanoplatforms that integrate imaging and therapeutic functions have received considerable attention as the next generation of medicine.”

The therapeutic component of this system is based on its ability to house, mask, and release selectively a drug cargo. There are numerous examples of polymeric or porous nanostructures that can non-covalently carry a drug cargo, and then release it slowly, like a “leaky bucket” or molecular sponge. Ours is different because the carrier is encased within a protective shell.